N-substituted p-benzenedisulfonamides



United States Patent N-SUBSTITUTED p-BENZEMDESULFGNAMIDES Gerald F. Holland and Wfiliam M. McLarnore, Groton, and Gerald D. Laulsach, Niantic, Comm, assignors to Chas, Pfizer & Co., Inc, New York, N.Y., a corporation of Delaware No Drawing. Filed June 29, 196i Ser. No. 3*),717 5 Claims. (Cl. 260-556) This inventon relates to new and useful disulfonamides in the benzene series. More particularly, it is concerned with novel N-substituted p-benzenedisulfonamides, i.e., 4- sulfamlbenzenesulfonamides, as well as with the alkali metal salts thereof. There is also included within the purview of this invention Various pharmaceutical compositions which have at least one of the herein described compounds as their essential active ingredient.

The compounds which are included Within the scope of this invention are selected from the group consisting of disulfonamides corresponding to the following general structural formulae:

Slog NH: II X l son?" and SO1NH2 SOZNHCRRC OORT and the alkali metal salts thereof, wherein X is a member selected from the group consisting of hydrogen, chlorine, bromine, nitro, cyano, trifiuorornethyl, lower alkylmercapto andlower alkylsulfonyl wherein in each instance the lower alkyl group has from one to four carbon atoms, alkoxyl having from one to four carbons and alkyl having from one to three carbon atoms; R is a member selected tom the group consisting of hydrogen, alkyl having from one to four carbon atoms, aminopropyl, aminobutyl, mercaptomethyl, S-methylmercaptoethyl, carboxymethyl, carboxyethyl, hydroxymethyl, u-hydroxyethyl, benzyl, p-hydroxybenzyl, p-hydroxyphenyl, carboxamidomethyl, 'y-carboxamidoaminopropyl, 7 guanidylpropyl, 4 imidazolemethyl and ,B-indolemethyl; R is a member selected from the group consisting of hydrogen and methyl, said R being methyl only when R is ethyl; R" is a member's:- lected from the group consisting of hydrogen, alkyl having from one to ten carbon atoms, amino, N-mono (lower)alkylamino, N,N-di(lower) alkylamine, hydrazino, N-mono- (lower) alkylhydrazino and N,N-di(lower)alkylhydrazino, wherein in each instance the lower alkyl group has from one to four carbon atoms; and R is a member selected from the group consisting of N-monoalkyl having from one to ten carbon atoms, N-monohalo(lower) alkylamino,

"ice

cycloheptylamino, N-monobenzylamino, N-mono B-phenylethyl) amino, N-mono (m-Xylyl) amino, N-mono (p-chlorobenzohydryl(amino, N-anilino, N-(m-tritluoromethylaniline), N-(p-toluidino), N-(p-anisidino), N-mono(anaphthyl)amino, N-mono(B-naphthyl)amino, l-pyrryl, 1- imidazoyl, l-pyrrolidyl, l-piperidyl, l-piperazyl, 1-(4- methylpiperazyl), 4-morpholinyl, 4-t-hiamorpholinyl, N,N- dibenzylamino and N,N-di(lower) alkylamino wherein said lower alkyl group has from one to four carbon atoms.

In accordance with the present invention, the aforementioned benzenedisulfonamides all exhibit interesting pharmacological properties which render them useful as synthetic medicinals. For instance, the compounds of this invention are extremely valuable as carbonic anhydrase inhibitors, i.e., they inhibit the activity of carbonic anhydrase and this, in turn, serves to depress the central nervous system and increase the amount of water and sodium excreted in the urine. Hence, thesecompounds are particularly useful for supressing excitability in animals and for protecting them against convulsive seizures or for combatting same. In addition, they can also be employed in the treatment of edema and like conditions in view of the diuretic properties which they possess, especially those compounds of the amino acid substituted type. Among the many typical examples of compounds included Within the purview of the present invention are N-rnonoisopropyl-p-benzenedisulfonamide, N monoallylp-benzenedisulfonamide, N-monocyclohexyl-p-benzenedi-' sulfonamide, N-monobenzyl-p-benzenedisulfonamide, N- (rn-trifluoromethylphenyl) p benzenedisulfonamide, N-

(a-naphthyl -p-benzenedisulfonamide, N- (4-sulfamylben ylbenzenesulfonyl)lysine,-N- (4-sulfamylbenzencsulfonyl)- glutamic acid, N (3-chloro-4-sulfarnylbenzenesulfonyl)- histidene, N-(4-sulfamylbenzenesulfonyl)tryptophane, and the like.

In accordance with the process for preparing the compounds of this invention, an appropriate 4-sulfamylbenzenesulfonyl chloride is treat% with a primary organic amine of the formula R"NH or with an u-amino acid type compound of the formula H NCRR'COOR" wherein a R, R, R", and R are all as previously defined. This N-monoalkyl having from two to'eight carbon atoms, N-

reaction can best be carried out in accordance with the general method of Q. Hinsberg et al. as originally re.-

ported in the Ohemische Berichte, vol. 23, p. 2962 (1890),

and ibid, vol. 38, p. 906 (1905), although in the case of the basic diaminoacids it is necessary that the second or non-a-amino group be first protected via conventional blocking techniques, e.g., by a carbobenzyloxy group. In the latter connection, it is preferable to first form a copper chelate salt of the desired diarnino acid and then treat the latter intermediate with, benzyl chloroforrnate, followed rials employed in this process are readily prepared fromi i the corresponding sulfanilamide compounds via the general procedure of H. Meerwin et al. as described in the Chemische Berichte, vol. 90, p. 841 (1957). In the present instance, this method involves first diazotizing the amino group of one of the aforementioned sulfanilamides and then treating the resulting diazonium salt so obtained with sulfur dioxide in a glacial acetic acid solvent medium containing cupric chloride at a temperature that is in the neighborhood of C., i.e., Within the range of from about 5 C. to. about C.

The alkali metal salts of the compounds of this invention are easily obtained. in accordance with conventional methods. In general, such methods involve dissolving the selected 4-sulfamylbenzenesulfonamide in an aqueous or alcoholic solution of an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, and concentrating. the resulting solution so obtained.

As previously indicated, the compounds of the presentv invention are readily adapted to therapeutic use as diuretic agents and/ or as anti-convulsants. Furthermore, .the toX- icity of these particular N-substituted p-benzenedisulfonamides has been found to be quite low when they are administered to mice in amounts that are sufiicient to achieve the desired therapeutic effects. Moreover, no other harmful pharmacological side effects have been observed to occur as a result of their administration.

In accordance with a method of treatment of the present invention, the herein described benzenedisulfonamide derivatives can be administered to an agitated subject via the oral or parenteral routes. In general, these compounds are most desirably administered in doses ranging from about 200 mg. to about 2000 mg. per day, although variations will necessarily occur depending upon the weight of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of from about 2.8 mg. to about 28.0

mg. per kg. of body weight per day is most desirably employed in order to achieve effective results. Nevertheless, it is to be appreciated that still other variations may also occur in this respect, depending upon the severity of the patients condition and its individual response to said medicament, as well as on the particular type of formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger dosages may be employed without causing any harmful or deleterious side effects provided that such higher levels are first divided into several smaller doses that are to be administered throughout the day.

In connection with the use of the benzenedisulfonamide compounds of this invention for the treatment of an epileptic subject, it is to be noted that they may be administered either alone or in combination with a pharmaceutically acceptable carrier. by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the novel compounds of this invention can be administered in awide variety of dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, loz enges, troches, hard candies, powders, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical compositions can be sweetened and/or flavored by means of various agents of l A. cient to provide the desired unit dosage previously indicated.

For purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft elastic and hardshelled gelatin capsules; preferred materials in this connection would also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as Water, ethanol, propylene glycol and glycerin, as well as various like combinations thereof.

For purposes of parenteral administration, solutions of the benzenedisulfonamides in sesame or peanut oil or in aqueous-propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding Watersoluble alkali metal salts previously enumerated. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent rendered isotonic with sufficient glucose or saline. These particular solutions are especially suitable for intravenous, intramuscular and subcutaneous injection purposes. Needless to say, the necessary steps should be taken throughout the preparation of these injectable solutions so as to ensure that final products are obtained in a sterile condition.

This invention is funther illustrated by the following examples, which are not to be construed as imposing any limitations on the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications and equivalents thereof which readily suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

Example I To 200 ml. of chlorosulfonic acid there is added 50 g. of dry o-chloroacetanilide with constant agitation being maintained throughout the addition. After the foaming subsides, the reaction mixture is heated to C. and maintained at that point for two hours. Upon removal of the excess chlorosulfonic acid via evaporation under reduced pressure, there is obtained a residual material which is subsequently treated with ice water. The precipitated product is then recovered by means of filtration, washed with water and air dried to constant weight.

To the 3-chloro-4-acetamidobenzenesulfonyl chloride prepared as described in the above manner, there is added a slight excess of concentrated ammonium hydroxide diluted with an equal amount of water. The resultant solution is slowly-heated with occasional stirring and maintained just below the boiling point for about five minutes. The pasty suspension which forms is cooled in an ice bath, filtered and the filter cake so collected is pressed dry on the funnel with the aid of suction. Upon recrystallization of the product from acetonediethyl ether, there is obtained pure 3-chloro-4-acetamidobenzenesulfonamide. Hydrolysis of the latter compound with dilute hydrochloric acid in. accordance with standard organic procedure affords 3-chloro-4-aminobenzenesulfonamide.

except that m-chloroacetanilide is the starting material employed. In this case, the latter compound is succes- 2-chloro 4 aminobenzenesulfonamide, respectively.

I sented below in order to avoid unnecessary repetition. In

each and every case, the corresponding sulfanilamide compound is the final product obtained.

o-Bromoacetanilide o-Methylacetanilide m-Nitroacetanilide o-Cyanoacetanilide m-lviethylmercaptoacetanilide m-Methylsulfonylacetanilide GIVEethOXyac-etanilide mdviethylacetanilide m-Cyanoacetanilide o-Nitroacetanilide m-Bromoacetanilide o-Ethylmercaptoacetanilide m-Ethylsulfonylacetanilide o-Ethoxyacetanilide o-Ethylacetanilide o-(n-Propylmercapto)ethylacetanilide mXn-Propylsulforiyl) ethylacetanilide rn-lsopropoxyacetanilide o- (n-rropyg acetanilide m (n-Butylrnercapto) acetanilide o-(n-Butylsulfonyl acetanilide o- (ri-Butoxy) acetanilide Example 111 In a 500 ml. three-necked, round-bottomed flask equipped with a mechanical stirrer, thermometer and dropping funnel, there is placed 76.8 g.'(0.372 mole) of 3 chloro 4 aminobenzenesulfonamide and 125 ml. of water. Stirring is initiated and 63 ml. (0.744 mole) of concentrated hydrochloric acid is rapidly added to the agitated slurry. After cooling the resulting solution to below C. by means of an aqueous acetone Dry-Ice bath, a saturated aqueous solution containing 26.5 g. (0.372 mole, 97% purity) of sodium nitrite is added via the dropping funnel at such a rate'that the temperature of the solution does not rise above 0 C.

The above diazonium solution is then rapidly added with stirring to 350 ml. of a saturated solution of sulfur be prepared in accordance with this example" form a large but yet determinable number of compounds, the following list of sulfonamide starting materials is presented below in order to avoid unnecessary repetition of experimental detaiL- In each and every case, the corresponding 4-sulfamylbenzenesulfonyl chloride is the; prodnot obtained.

' 3-bromo-4-aminobenzenesulionarnide 2-nitro-4-aminobenzenesulfonamide 3-cyano-4-aminobenzenesulfonamide Z-methylmercapto-4-aminobenzenesulfonamide,

v 2-methylsulfonyl-4-aminobenzenesulfonamide 3-methoXy-4-aminobenzenesulfonamide 2-rnethyl-4-aminobenzenesulfonarnide 2-cyano-4-aminohenzenesulfonamide 3-nitro-4-aminobenzenesulfonamide Z-bromo-4-aminobenzenesulfonamide -3-ethylmercapto-4 arninobenzenesulfonamide Z-ethylsulfonyl-4-aminobenzenesulfonamide 3-ethoxy4 aminobenzenesulfonamide 3-ethyl-4=aminobenzenesulfonamide v I 3-(rt-propyl)mercapto 4-aminobenzenesulfonamide Z-(n-propylsulfonyl)-4-aminobenzenesulfonamide 2-isopropoxy-4-aminobenzenesulfonamide 3 (n-propyl -4-aminobenzenesulfonarnide 27(n-butylmercapto) 4-aminobenzenesulfonarnide 3 -(n-butylsulfonyl 4-i1minobenzenesulfonamide 3- (n-b utoxy)-4-aminobenzenesulfonamide Example V round-bottomed flask equipped with mechanical stirrer, thermometer and reflux condenser there is added 801111.. of a 1N sodium hydroxide solution. Stirring is commenced and when complete vsolutionis 'efiected there is then'added g. (0.039 mole) of ,4-sulfarnylbenzene:

sulfonyl chloride in'small portionsduringdhe course of a fifteen minute period. Vigorous agitation is then maintained for an additional hour with the necessary precautions being taken to maintain the temperature of the reaction mixture 'in the -20" C. range. The reaction solution is also testedfrom time to time throughout this dioxide in glacial acetic acid (-25% by weight) to which a'saturated aqueous solution containing g. of cupric chloride dihydrate had already been added. Upon completion of this step, the ice-bath is removed and the reaction mixture is stirred for about ten minutes at room temperature. The precipitated product is then collected by means of filtration and washed Well with cold water. In this manner, there is obtained pure crystalline 2-chloro- 4-sulfamylbenzenesulfonyl chloride.

V Example IV I V /hen 2-chloro-4-aminobenzenesulfonamide is the starting material employed in the reaction prlocedureof the foregoing example, the corresponding product obtained is 3 chloro 4 suliamylhenzenesulionyl chloride. In like manner, 3-trifiuoromethy1-4-aminobenzenesulfonamide is converted to Z-Irifiuoiom'ethyl 4 aminobenzenesulfonyl chloride; 2-trifiuoromethyl-4-aminobenzenesulfonamide is except that derivatives of glycine are individually ernperiod to be certain-that it is still basic to litmus paper. Upon completion of this step, the reaction mixture is cooled and filtered, and the resulting filtrate aoidified with concentrated hydrochloric acid. After allowing said solution to stand overnight in an icebox,'crystallization of the desired product slowly occurs (this process can be mastened by scratchingthe walls of the glass container with a stirring rod). The crystalline product is then collected by means of filtration, washed with water and air driedto afford an 81% yield'of N-4-sulfamylbenzenesulfonyD-glycine, MP. 234-235" C. AiiaZysis. -Ca1cd. for C H bN O s i C, 32.65; H.342; N. 9.52. Found: C,'32.6l; H, 3.55; N, 9.63. V

V v Example VI. 7 V) V The procedurefdescribed in ExamplefV is followed except for the fact that the amino acid employed is alanine instead of glycine. Thus, when equimolar amounts of 4-suliamylbenzenesultonyl. chloride and alanine react in accordance with this procedure, there is'pbtained a 28% yield of N-(4-sulfamylbenzenesulfonyl)alanine, MP.

Analysis-Ca led. for C H N 0 S C, 35.06; H, 3.92; N, 9.09. Found: C, 34.75; H, 3.87; N, 9.05 i

, g Example VII '7 The procedure described in Example v is" followed ployed as starting materials in lieu of the parentacid: itself.

Thus, when eqnim'olar amounts of' 4-sulfamylbenzei t "sulfonyl'chlorideand glycine ethyl esterreact in accord *ance'with this'procedure, there is obtained a 52% yield of To 3 g. (0.039 mole of glycine contained ina 200 ml, I

3,1 7 N-(4-sulfamylbenzenesulfonyl) glycine ethyl ester, M.P. 184-185 C.

Analysis.Calcd. for C H N O S C, 37.26; H, 4.38; N, 8.69. ,Found: C, 37.12; H, 4.45,; N, 8.65.

In. like manner, equimolar amounts of 4-sulfamyl- .benzenesulfonyl chloride and glycine amide react to afford react to afford a 95% yield of N-(4-sulfamylbenzene sulfonyl) glycine N-(n-propyDamide, M.P. 145-l46 C.

Analysis.-Calcd. for C H N O S C, 39.39; H, 5.11; N, 12.53. Found: C, 39.20; H, 5.37; N, 12.51.

Example VIII amounts of this particular sulfonyl chloride and glycine react in accordance with the reaction conditions of this procedure, the correspondingproduct obtained is N-(2-- In like chloro 4 sulfamylbenzenesulfonyl) glycine. manner and employing 'equimolar amounts of starting material and reagent in each case, 3-chloro-4-sulfamylbenzenesulfonyl jchloride and alanine react to afford N r (3 chloro 4 sulfamylbenzenesulfonyl)alanine; Z-triiluororuethyl-4-sulfamylbenzenesulfonyl chloride and alanine react to afford N-(Z-trifluoromethyl-4-sulfamylbenzenesulfonyl)alanine; 3 trifluoromethyl-4-sulfamylbenzenesulfonyl chloride and aline react to afford N+(3- trifluoromethyl 4 sulfamylbenzenesulfonyl)aline; 4- sulfamylbenzenesulfonyl chloride and aline react to afiord N (4 sulfamylbenzenesulfonyl)aline; 2 bromo 4- sulfamylbenzenesulfonyl chloride and norvalinereact to afford N (2 bromo 4 sulfamylhenzenesulfonyl) norvaline; 3-nitro-4-sulfamylhenzenesulfonyl chloride and norvaline react to afford N-(3-nitro-4-sulfamylbenzenesulfonyl)norvaline; 2-cyano 4 sulfamylbenzeneaulfonyl chloride and leucine react to afford N-(2-cyano-4- sulfamylbenzenesulfonyl)leucine; 3 methylmercapto-4- sulfamylbenzenesulfonyl chloride and leucine react to afford N (3 methylrnercapto 4 sulfamylbenzenesulfonyl)leucine; 3 methylsulfonyl 4 sulfamylbenzenesulfonyl chloride and norleucine react to afford N-(3- methylsulfonyl 4 4 sulfamylbenzenesulfonyl)norleucine; 2 methoxy 4 sulfamylbenzenesulfonyl chloride and norleucine react to afford N-(2-methoxy-4-sulfamylbenzenesulfonyhnorleucine; 3 methyl 4 sulfamylbenzenesulfonyl chloride and isoleucine react. to afford N-(3- methyl 4 sulfamylbenzenesulfonyl)isoleucine; 2 trifiuoromethyl' 4 sulfamylbenzenesulfonyl chloride and isoleucine react to aiford N-(2-trifiuoromethyl-4-sulfamylbenzenesulfonyl)isoleucinc; 3 cyano 4 sulfarnylbenzenefonyl chloride and isovaline react to afford N-(3- cyano 4 sulfamylbenzenesulfonyl)isovaline; 2 nitro- 4-sulfamylbenzenesulfonyl chloride and isovaline react to afford N (2 nitro 4 sulfamylbenzenesulfonyl)isova line; 2-chloro-4-sulfamylbenzenesulfonyl chloride and phenylalanine react to afford N-(2-chloro-4-sulfamylben zenesulfonyl)phenylalanine; 3 bromo 4 sulfamyl benzene'sulfonyl chloride and phenylalanine react to afford N (3 bromo 4 sulfamylbenzenesulfonyl)phenylalanine; 2 ethylmercapto 4 sulfamylbenzenesulfonyl chloride andtyrosine react to afford N-(Z-ethylmercaptomethyl 4 sulfamylbenzenesulfonyl)tyrosine; 3 ethylsulfonyl-4-sulfamylbenzenesulfonylchloride and tyrosine 8 react to aiford N-(3-ethylsu1fonyl-4-sulfamylbenzenesulfonyDtyrosine; 2 ethoxy 4 sulfamylbenzenesulfonyl chloride and serine react to aiford N- (2-ethoxy-4-sulfamylbenzenesulfonyl)serine; 2 -etl1yl 4 sulfarnylbenzenesulfonyl chloride and serine react to afiord N-(2-ethyl-4- sulfamylhenzenesnlfonyl)serine; 3 bromo 4 sulfamylbenzenesulfonyl chloride and a-amino-fi-hydroxybutyric acid react to afford a-[N-(3-bromo-4-sulfamylbenzenesulfonybamino] 3 hydroxybutyric acid; 2 cyano 4- sulfamylbenzenesulfonyl chloride and u-amino-fi-hydroxybutyric acid react to atiord a-[N-(2-cyano-4-sulfamylbenzenesulfonyl)amino]- 3-hydroxybutyric acid; 3-nitro-4- sulfamylbenzenesulfonyl chloride and cysteine react to afiord N (3 nitro 4 4 sulfamylbenzenesulfonyl)- cysteine; 4-sulfamylbenzenesulfonyl chloride and cysteine react to afford N (4 sulfarnylbenzenesulfonyl)cysteine; 2 (n propylmercapto) 4 sulfamylbenzenesulfonyl chloride and methionine react to afford N-[2-(n-propylmercapto) 4 sulfamylbenzenesulfonyl]methionine; 3- (n-propylsulfonyl) 4 sulfamylbenzenesulfonyl chloride and methionine react to afiford N-[3-(n-propylsulfony1)- 4 sulfamylbenzenesulfonyl]methionine; 2 trifluoromethyl-4-sulfamylbenzenesulfonyl chloride and aspartic acid react to aiford N-(2-trifluoromethyl-4-sulfamylbenzenesulfonyDaspartic acid; 3 isopropoxy 4 sulfamylbenzenesulfonyl chloride and aspartic acid react to afford N (3 isopropoxy 4 sulfamylbenzenesulfonyl)aspartic acid; 2 (n propyl) 4 sulfamylbenzenesulfonyl chloride and glutamic acid react to afiord N-[2-(npropyl 4- sulfarnylhenzenesulfonyl] glutamic acid; 4-

sultamylbenzenesulfonyl chloride and glutamic acid react to afford N-(4-sulfarnylbenzenesulfonyl)glutamic acid; 3- chloro-4-sulfarnylbenzenesulfonyl v chloride and arginine react via the corresponding 6-guanidyl carbobenzyloxy derivative of said diamino acid to afford N-(3-chloro-4- sulfamylbenzenesulfonyl) arginine; 2 bromo-4-sulfamylbenzenesulfonyl chloride and arginine react via thecorresponding a-guanidyl carbobenzyloxy derivative of said diamino acid to afford N-(2-bromo-4-sulfamylbenzenesulfonyl)arginine; 3 nitro 4 sulfamylbenzenesulfonyl chloride and lysine react via the corresponding e-aminocarbobenzyloxy of said diamino acid to aiford N-(3-nitro- 4 sulfamylbenzenesulfonyl)lysine; 4 sulfamylbenzenesulfonyl chloride andlysine react via the corresponding e-Zl'llil'lO carbobenzyloxy derivative of said diamino acid to afiord N (4 sulfamylbenzenesulfonyl)lysine; 2- cyano-4--sulfamylbenzenesulfonyl chloride and ornithine react via the corresponding ,fi-aminocarbobenzyloxy derivative of said diamino acid to afford N-(2-cyano-4- sulfamylbenzenesulfonyl)ornithine; 3 (n butylmercapto)-4-sulfamylbenzenesulfonyl and ornithine react via the corresponding -6-amin0carbobenzyloxy derivative of said diamino acid to afford N-[3-(n-butylmercapto)-4 sulfamylbenzenesulfonyl]orithine; 2 (n butylsulfonyD- 4-sulfan1ylbenzenesulfonyl chloride and asparagine react to afford N [2 (n hutylsulfonyl) 4 sulfamylbenzenesulfonyl] asparagine; 3 trifluorornethyl 4 sulfamylbenzenesulfonyl chloride and asparagine react to afford 'N (3 trifluoromethyl 4 sulfamylbenzenesulfonyl)- asparagine; 2 (n butoxy) 4 sulfamylbenzenesulfonyl chloride and citrulline react to afford N'-[2-(n-butoXy)-4- sulfamylbenzenesulfonyl]citrulline; 2-methyl-4-sulfamylbenzenesulfonyl chloride and citrulline react to afiord 'N (2 methyl 4 sulfamylbenzenesulfonyl)citrulline; 3-chloro-4-sulfamylbenzenesulfonyl chloride and histidine react to aiford N (3 chloro 4 snlfamylbenzenesulfonyl)histidine; 2 bromo 4 sulramylbenzenesulfonyl chloride and histidine react to afford N-(2-bromo-4 sulfamylbenzenesulfonyl)histidine; 3 nitro 4 sulfamylbenzenesulfonyl chloride and tryptophanereact to afiord N (3 nitro 4 sulfamylbenzencsulfonyl)tryptophane; and 4-sulfamylbenzenesulfonyl chloride and tryptophane react to afford N- (4-sulfamylbenzenesulfonyl)tryptophane. I

except that other Starting materials of the type employed in Example V11 are individually used. Inasmuch as the other amino acids employed in Example VIII also form these same type derivatives, the products prepared in this particular example form a large but determinable number of compounds. Accordingly, the following list of ester, amide and hydrazide derivatives of alanine is hereinafter presented, in order to avoid unnecessary repetition of experimental details, although it is to be understood that similar type derivatives of the other rat-amino acids listed as starting materials in Example VIII are equally applicable in the present instance. The ester derivatives of alanine so employed include the following lower alkyl esters thereof: methyl, ethyl, isopropyl, r1-butyl, isoamyl, n-hexyl, Z-ethylhexyl, n-octyl and n-decyl. The amide derivatives of alanine so employed include the parent glycine amide as well as the following N-monoalkyl and ILN-dialkyl derivatives thereof: N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide, N-isopropylcarboxamide, and N,N-di(n-butyl)carboxamide. The hydrazide derivatives of alanine so employed include alanine hydrazide itself as well as the following N-monoalkyl and N,N-dialkyl derivatives thereof: N,ll-dhnethylcarhohydrazide, N-ethylcarbohydrazide, N-isopropyicarbohydrazide, and N,N-di(n-butyl)carbohydrazide.

Example To 2.3 g. (0.039 mole) ofisopropylarnine contained in a 200ml. round-bottomed-r'iask equipped with mechanical stirrer, thermometer and reflux condenser there is added 30 ml. of a aqueous sodium hydroxide solution. Stirring is commenced and-when complete solution is effected there is then added 10 g.- (0.039 mole) of 4- sulfamylbenzenesulfonyl chloride in small portions during the course of fifteen minute period. The remainder of the'procedure, including the isolation step, is essentially the same as that described in Example IV. In this manner, there .is obtained a 71% yield of .N-monoism propyl-p-benzenedisplfonamide, M.P. 167-468" C; A v

it Analysis.Calcd. 01 C13H14N2O4S2: C, H, N, 8.58. Found: C, 47.90; H, 4.14; N, 8.49.

I Example XIV The procedure described in Example is followed except that m-trifiuoromethylaniline is the starting material employed in lieu of isopropylamine. .Thus, when equimolar amounts of 4-sulfamylbenzenesulfonyl chloride and m-triiiuoromethylaniline react in accordance with this procedure, there is obtained a 52% yield of N-(m-trifluoromethylphenyl)-p-benzenedisulfonamide, M.P. 167- 168 C.- V

AIZCZILYSlS- CfilCd. for C13H11F3N204S2: C, H, 2.92; N, 7.37. Found: C, 40.71; H, 2.77; N, 7.66.

Example XV The procedure described in Example X is followed except that or-naphthylarnine is the starting material embenzenedisulfonamide, M.P. 241-242 C- 38.73; H, 4.99; N,"10.l3.

N, 10.07. Found: C,

Example XI 2 The procedure described in Example followed except for the fact that allylarnine is the starting material employed 'in place of the isopropylarnine used inthe 7 previous example. Thus, when equimolaramounts of 4-sulfamylhenzenesulfonyl chloride and allylamineueact in accordance with this procedure, there is obtained a-69% in lieu of -is'opropylamine.

yield of N-monoallyl-p-ben'zenedisultonamide, M.P.

Analysis.Calcd. for C H N O S C, 39.l1;'H, 4.3 8; N, 10.14. Found: C, 39.01; H, 4.45; N, 9.89. a

Thepr 'ocedure described in Example X followed except that cyclohexylamine is the starting material employed in lieu of isopropylaminel Thus, when'equirnolar amounts of '4-sulfamylbenzenesulfonyl chloride andcyclo hexylamine react in accordance with this procedue, there 17' N, 8.80. Found: C, 44.92; H, 5.66;;N, 9.20.; f

Example X111 amounts of 4-sultamylbenzenesulfonyl chloride and benzylarnine react in accordance with this procedure, there is obtained 21 yield of N-monobenayhp-benzenedisulfonamide, M.P. 196-197 C.

chloride and methylamine react in accordance with this procedure, there is obtained a 61% yield of N-monomethyl-p-benzetiedisulfonamide, M.P. 158159- C.

AnalysisP-Calcdl forC l-l N O s z C, 33.59; H, 5.03;

N, 11.19. Found C, 33.85; H, 4.13; N, 11.40.

l Example XVII V The procedure described in Example 'X is followed N except that fi-hromoethylamine is the starting material emple-yedin lieu of isopropylamine. Thus, when equimolar amounts of 4-sulfarnylbenzenesulfonyl chloride and B-hromoethylamine react .in accordance with this procedure, there. is obtained a 63% yield of Isl-monom- "hromoethyn-p-benzenedisulfonamide, M.P. 154-155 C. 3

ExampleyXVHI The procedure described in ExampleX is followed except that piper'idine is the starting material employed 7 Thus, when equirnolar amounts of4-sulfamylbenzenesulfonyl chloride and piperdinereactin accordance with this procedure there is .obtainezta 48% yield of N-piperidyl-p-benzenedisulfon- The procedure described inExample IX is followed} -except that 'diberriylamine :is the starting material em- 'ployed in lieu of isopropylamine. amounts of 4-sulfamylhenzenesnlfonyl chloride and dibenzylarnine react in accordance with this procedure, thereis obtained a 27% yield of N,N-dibenzyl-p-benzenedisulfonamide,l78 l79Cf Analysis.Calcd for C H N O S C, 57.67; H, 4;84; 0 N, 6.73; Found: C,"57.54;.H,'4.89; N, 6.80;

The procedure described in Example. X isfollowed p except'that benzylarnine is thestarting material employed in lieu of isopropylamine Thus, when equirnolar .Exaniple [The procedure described in Example X is essentially ff followed except that other. amine starting materials of: l the type used in Examples X-XIX are individually ensployed inthe present instance in lieu ofisopropylamine. Inasmuch as the'pr'oducts prepared in this. example form g Thus, when equimolar.

benzenesulfonyl chloride.

a large butyet determinablenumber of compounds, the following list of amine starting materials is presented below in order to avoid unnecessary repetition of experimental details. In each and every case, thecorrespending N-substituted p-benzenedisulfonamide is the final product obtained:

Ethylamiue (33% in water),fi-Phenylethylamine n-Propylamine m-Xylylamine Isobutylamine p-Chlorobenzohydrylamine n-Butylamine Aniline Isoamylamine p-Toluidine n-Amylamine p-Anisidine n-Hexylamine p-Naphthylamine n-(2-ethyl)hexylamine Pyrrole n-Decylamine Imidazole -Chlorobutylamine Piperazine 'y-Iodopropylamine Pyrrolidine Vinylamine 4-Methylpiperazine fi-Methallylamine Morpholine 2-octenylamine-1 Thiomorpholine Cyclopropylamine Dimethylamine in Cyclopentylamine Water) Cyclobutylamine Diethylarnine Cycloheptylamine Di-isopropylamine Di- (n-butyl) amine Example XXI The procedure described in Example X. is followed except that the 4-sulfamylbenzenesulfonyl chloride starting materials used in Example VIII are also individually employed in the present instance for just such purposes in' lieu of 4-sulfamylbenzenesulfonyl chloride. Such sulfonyl chloride starting materials specifically include 2- ch1oro-4-sulfamylbenzenesulfonyl chloride, 3-chloro-4- sulfamylbenzenesulfonyl chloride, 2-trifiuoro-4-su1famylbenzenesulfonyl chloride and 3-trifluoromethyl-4-sulfamyl- In each case, the corresponding ring substituted N-monoisopropyl-p-benzene-disu1fonamide is the product obtained.

Example XXII 2,730,534: 1/56 Hoefie 260- 556 -2,965,655 12/60 Novello a. 260556 3,019,245 1/62 Novello '260556 3,050,553 8/62 Novello 260 -2934 FOREIGN PATENTS w 364,408 11/38 Italy.

react with anyone of the foregoing hydroxides to afford the corresponding alkali metal salts. In all of these cases, the salts so formed are especially suitable for. the preparation of injectable aqueous solutions as'previously indicated in the specification.

v ExampleXXlII A dry solid pharmaceutical composition is prepared by blending fthefollowing materials in the proportions by weight specified:

N-monobenzyl-p-benzenedisulfonamide 1O Potato starch 20 Dicalcium phosphate, a 45 Lactose 15 Polyvinylpyrrolidone 8 Magnesium stearate 2 After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such size that it contains mg. of the active ingredient.

Example XXIV A dry solid pharmaceutical composition is prepared by combining the following materials in the proportions by Weight specified:

N-monoisopropyl-p-benzenedisulfonamide l0 Polyethylene glycol (average molecular weight, 6060)- 30 Lactose 40 Calcium carbonate 20 The dried solid mixture so prepared is thoroughy agitated so as to obtain a powdered product that is completely uniform. Soft elastic and hard-shelled gelatin capsules containing this pharmaceutical composition are then prepared employing' a sufficient quantity of material so as to furnish 250 mg. of the active ingredient in each capsule.

Example XXV An aqueous propylene glycol solution containing the monosodium salt of N-(4-sulfamylbenzenesulfonyl) glycine is prepared by dissolving the latter compound in propylene glycol-water (1:3 by Weight) with the aid of gentle heating. The amount of compound employed is such that the resulting solution contains 5 mg. of the active ingredient per ml. perature, it is sterilized by means of filtration through a Seitz filter. The sterile aqueous propylcneglycol solu tion so obtained is suitable for intramuscular administration to animals.

What is claimed is:

1. N-monoallyl-p-benzenedisulfonamide.

2. N-monocyclohexyl -p-benzenedisulfonamide.

3. N-monobenzyl-p-benzenedisulfonamide.

4. N-mono (m trifiuoromethylphenyl) p benzenedL sulfonamide. i

5. N-mono(a-nap thyl) 'benzenedisulfonamide.

References Cited by the Examiner UNITED STATES PATENTS OTHER REFERENCES Raghaven et al.:'Current Science, vol. 16, pages 344- 345 (1947) Raghaven et al.: Chem. absts, vol. 43, col. 4-237 (1949). Raghaven et al.: Chem. Abstracts, vol. 47, col 6889 IRVING MARCUS, Primary Examiner.

H. 1., LIDOFF, D. T. MCCUTCHVEN,.WALTER A. MODANQE, Examiners. v V

After cooling to room tern. 

1. N-MONOALLYL-P-BENZENEDISULFONAMIDE.
 2. N-MONOCYCLOHEXYL-P-BENZENEDISULFONAMIDE.
 3. N-MONOBENZYL-P-BENZENEDISULFONAMIDE.
 4. N-MONO (M-TRIFLUOROMETHYLPHENYL) - P - BENZENEDISULFONAMIDE.
 5. N-MONO(A-NAPHTHYL)-P-BENZENEDISULFONAMIDE. 